We are investigating the pathogenesis and nosologic relationships of neuromuscular lesions induced by vitamin E deficiency in experimental animals and in humans. Our observations indicate that the pathogenesis of these lesions involves a selective injury of cell membranes, especially mitochondria and sarcoplasma reticulum, associated with excessive catabolism of membrane phospholipids and increased membrane permeability. The development of axonal lesions in E-deficient mammals probably involves "dying-back" processes. In the proposed studies biochemical changes in cell membrane constituents (including phospholipids and enzymes) of skeletal muscle, neural tissue, and CNS endothelium will be correlated with accompanying histologic, histochemical, and ultrastructural alterations in these tissues during the induction and resolution of E-deficiency in experimental animals. The sites of the earliest lesions and axonal transport characteristics in E-deficient mammalian axons will be delineated. Ionophores will be used to detect latent changes in membrane permeability. Tissue culture systems will facilitate these studies. Detailed morphologic comparison of postmortem neuromuscular tissues from humans with chronic vitamin E deficiency or spinocerebellar degenerations, and from E-deficient animals will identify similar pathogenetic mechanisms. The role of cell membrane injury and axonal dying-back processes in the pathogenesis of neuromuscular lesions in young, E-deficient, warm-blooded vertebrates including humans will be elucidated. Pathogenetic relationships between E-deficiency myeloneuropathy and other experimental or human degenerative myeloneuropathies will be identified. Relationships between biochemical alterations in CNS microcirculatory injury and impaired vascular permeability will be delineated.